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Blogs

03/08/2017.Statins4Drusen

Age-Related Macular Degeneration (AMD) is the most common cause of legal blindness in developed countries in the over-50s. One of the distinguishing characteristics of the early and intermediate stages of the disease are drusen. These are yellowish deposits, composed principally of lipids and proteins, which are formed in the retina and contribute to the development of AMD.

There are indications that abnormal levels of systemic cholesterol may be linked to the formation of drusen. This is why the Barcelona Macula Foundation (BMF) in conjunction with the Institut de la Màcula (IM) will conduct a study to determine whether the use of high doses of statins (drugs that inhibit the biosynthesis of cholesterol) lead to a regression or reduction in the volume and number of drusen in patients with intermediate AMD after 24 months.

This project, entitled STATINS4DRUSEN, may help to provide a new therapy that delays the progression of AMD, which is the priority aim of much research being conducted throughout the world.

The microbiome comprises microorganisms that live in or on the human body. There are a growing number of studies that link the microbiome to metabolic disorders through modulation of the inflammation, including inflammatory bowel disease, cancer, HIV/AIDS, schizophrenia and ageing.

With regard to the eye, the study of the microbiome relates principally to dry eye and autoimmune uveitis. Unfortunately, its role in Age-Related Macular Degeneration (AMD), the leading cause of blindness in developed countries in the over-50s, or in other eye disorders, has not been widely studied.

The Barcelona Macula Foundation (BMF), in conjunction with the Centre of Genomic Regulation (CRG) and the Institut de la Màcula (IM), will undertake the Microbiome Project in order to study the microbiome. The aim is to shed light on the mechanisms of AMD and to open up new channels for the creation of new therapies.

To do so, we will obtain stool samples from patients who attend the IM and who have a range of eye disorders. This will enable us to determine the association between gut microbiome and eye disease.

Methods This was a retrospective analysis of data from a prospective, natural history study of patients with GA who were followed for ≥6 months. Cluster analysis was used to identify subgroups within the population based on the presence of several phenotypic features: soft drusen, reticular pseudodrusen (RPD), primary foveal atrophy, increased fundus autofluorescence (FAF), greyish FAF appearance and subfoveal choroidal thickness (SFCT). A comparison of features between the subgroups was conducted, and a qualitative description of the new phenotypes was proposed. The atrophy growth rate between phenotypes was then compared.

Results Data were analysed from 77 eyes of 77 patients with GA. Cluster analysis identified three groups: phenotype 1 was characterised by high soft drusen load, foveal atrophy and slow growth; phenotype 3 showed high RPD load, extrafoveal and greyish FAF appearance and thin SFCT; the characteristics of phenotype 2 were midway between phenotypes 1 and 3. Phenotypes differed in all measured features (p≤0.013), with decreases in the presence of soft drusen, foveal atrophy and SFCT seen from phenotypes 1 to 3 and corresponding increases in high RPD load, high FAF and greyish FAF appearance. Atrophy growth rate differed between phenotypes 1, 2 and 3 (0.63, 1.91 and 1.73 mm2/year, respectively, p=0.0005).

Conclusion Cluster analysis identified three distinct phenotypes in GA. One of them showed a particularly slow growth pattern.

Purpose

To describe a subgroup of subjects with soft drusen associated with geographic atrophy (GA) and novel spectral-domain OCT (SD-OCT) findings consistent with presumed drusen leakage. We also propose a mechanism leading to GA progression in these patients.

Design

Participants

Methods

Drusen were evaluated with SD-OCT and retinal imaging to characterize the development of atrophy-associated drusen regression (drusen collapse) over a follow-up period of ≥18 months.

Main Outcome Measures

The presence of isoreflective dots at the outer retinal layers associated with retinal pigment epithelium (RPE) defects. Percentages of previously reported hyperreflective RPE, and hyperreflective dots (HRDs) were also determined.

Results

Nineteen of 48 eyes (39.6%) showed a collapse of ≥1 druse during the follow-up period. Thirty-four foci of collapsed drusen were found to be associated with either isoreflective dots associated with RPE defects (32.4%), hyperreflectivity of the RPE (91.2%), or HRDs (79.4%). A post hoc showed the adjusted odds ratio of drusen collapse for isoreflective dots (65.8), for HRDs (6.0) or both (12.1).

Conclusions

In soft drusen progressing to subsequent atrophy, approximately 33% were associated with isoreflective dots and RPE defects. In addition, overlying hyperreflectivity of the RPE and HRDs were noted with high frequency. Presence of isoreflective dots, with or without HRDs, was associated with a strong risk of developing atrophy compared with drusen without these findings. We hypothesize that these isoreflective dots associated with RPE defects may be debris extruded from the soft drusen into the subretinal space, which we have termed “drusen ooze”. Drusen ooze may activate the RPE apical surfaces, leading to a marked increase in phagocytosis/endocytosis of extracellular debris that eventually overwhelms the RPE capacity, and leads to RPE death, subsequent release of intracellular RPE material and thereby propagate a cycle of cellular death resulting in GA development and progression. Therapeutic targeting of drusen material, prior to its extrusion into the subretinal space and prior to irreversible damage to the RPE, might prevent or delay onset and progression of GA.

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Publication

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